Mixed HPV-related Neuroendocrine Carcinoma and HPV-related Squamous Cell Carcinoma of the Base of Tongue in a Patient With Incidental Identification of Synchronous Metastatic Papillary Thyroid Carcinoma

Discussion

While overall occurrence of HNC has declined in the US, the incidence of oropharyngeal cancer associated with HPV has risen steadily, the majority of which are SCC (1). HNCs can be difficult to diagnose because occult primary neoplasms are not uncommon, making the differentiation of primary from metastatic tumor especially important in the analysis of small tissue samples. In the presented case, most pre-operative tumor samples came from the cervical lymph nodes; thus, a major concern was metastasis from another site. The diagnosis of metastatic disease was based on clinical, morphological, and immunohistochemical evidence. Classically, HPV-related SCCs of the oropharynx, an HNC primarily seen in middle-aged men, present as cystic and painless neck masses with small primary lesions in the tonsil or base of the tongue. These neoplasms often appear similar to benign tonsillar crypt epithelium but will demonstrate moderate to strong p16 staining (3). The strong, diffuse nuclear and cytoplasmic p16 immunoreactivity of our case pointed toward an oropharyngeal primary, especially in the context of a negative EBER helping to exclude lymphoepithelial carcinoma of nasopharyngeal origin.

Additionally, a thyroid papillary carcinoma was identified in a separate lymph node, although no discernable thyroid mass was seen clinically or in imaging. Based on previous studies, metastatic thyroid carcinoma is an incidental finding in 0.3-7.9% of cases of head and neck lymph node dissection (4). In this case, the identified neoplasm demonstrated follicular formation lined by enlarged and overlapping cells with nuclear clearing, grooving and intranuclear pseudoinclusion, which are classic features of papillary thyroid carcinoma. The diagnosis was further supported by the strong, diffuse thyroglobulin, transcription termination factor 1 (TTF1), and paired box 8 protein (PAX8) immunoreactivity seen within the tumor.

From surgically resected tissue, the additional SCNEC was discovered intermixed with the SCC in the base-of-tongue tumor. HPV-related SCNEC arising in the oropharynx is rare, with fewer than 20 cases documented in literature (5). These neoplasms can be difficult to distinguish from non-keratinizing HPV-related SCC and metastatic SCNEC. The histological differences between SCNEC and SCC helped identify this synchronous (6, 7) and collision tumor even on the frozen section, which demonstrated nuclear peripheral palisading pattern and other nuclear features such as finely dispersed chromatin, no distinct nucleoli, molding, smudging, and frequently apoptotic bodies. Testing for neuroendocrine markers such as synaptophysin, chromogranin and CD56 typically are also helpful (3). This differential is clinically relevant because while HPV infection is associated with a good prognosis in oropharyngeal SCC, HPV may imply aggressive clinical behavior in SCNEC (5). Also important was differentiating between primary SCNEC and metastatic disease, which often relies more on clinical and radiological findings than pathological ones. In this case, immunohistochemistry identified the SCNEC as being separate from the SCC within the collision tumor, and because of the HPV positivity with a lack of other radiological findings, the SCNEC was considered a primary neoplasm.

Of note, SCNEC was not identified within the pre-operative lymph node biopsy and was only discovered from the surgically resected tissue, attesting to the diagnostic challenges of small tissue sampling. Although there is continued investigation on the most effective treatment modality for HPV-positive oropharyngeal cancer, this case demonstrates the value of surgical treatment in increased diagnostic accuracy, which can affect the post-operative clinical management. The diagnosis of SCNEC within the collision tumor in this patient drove clinical decisions to administer additional adjuvant chemotherapy, which may have contributed to the positive response to treatment seen in PET/CT.

In summary, we present an unusual case of a patient presenting with a collision tumor of the base of the tongue consisting of HPV-related SCC and HPV-related SCNEC and a synchronous metastatic papillary thyroid carcinoma in a neck lymph node. This case demonstrates the importance of tumor morphology and immunohistochemical testing in HPV-related oropharyngeal carcinomas, despite the overall good prognosis of such tumors, due to the possibility of synchronous or colliding primary neoplasms.